[unreadable] Severe systemic sclerosis (SSc) is a potentially fatal autoimmune disease. For patients with diffuse [unreadable] cutaneous SSc with internal organ involvement, 5-year survival is approximately 50%. Available therapies for refractory SSc remain inadequate and none are curative. It is hypothesized that allogeneic hematopoietic cell transplantation (HCT) will result in a sustained remission by the elimination of the autoreactive host immune effector cells or modulation of the activity of residual host immune effector cells if mixed hematopoietic chimerism is established. Recent studies of high-dose immunosuppressive therapy (HDIT) and autologous HCT for SSc have shown promise, but not all patients will tolerate HDIT, relapses have occurred, and long-term control is uncertain. In preclinical studies and clinical case reports, long-term disease control of autoimmune disease was better achieved with allogeneic than with autologous HCT. New methods of performing allogeneic HCT with low-intensity conditioning regimens which include fludarabine and total body irradiation offer the opportunity to investigate the effect of allogeneic HCT with reduced risk of treatment-related mortality. Survival of 85-90% is being reported now in many clinical trials of allogeneic HCT from HLA-identical sibling donors for nonmalignant diseases. For those patients who develop graft-versus-host disease, most will discontinue immunosuppressive therapy after 3-5 years. A significant response in the skin and disease stabilization has been observed in 3 patients with SSc after allogeneic HCT. In the most extensively studied patient followed for 5 years, there was skin remodeling with almost complete resolution of the dermal fibrosis and re-establishment of the microvasculature. We propose to conduct a phase 2 study of allogeneic HCT after nonmyeloablative conditioning in patients with severe systemic sclerosis. End points will be safety and response of the disease to the allogeneic cell graft (graft vs. autoimmunity). Mechanistic studies are proposed to investigate the response of the SSc-related autoantibodies, fibrosis, and vasculopathy to allogeneic HCT. We will also investigate the response of microchimerism to allogeneic HCT and the association to clinical response. If successful, we will have developed an effective therapy of systemic sclerosis which can improve quality of life and survival. The unique observations in this study regarding responses and recovery of organs after inducing a sustained remission of SSc will serve to focus and direct other non-transplant research activities. [unreadable] [unreadable] [unreadable]